Chronic Obstructive Pulmonary Disease (COPD) is diagnosed by pulmonary function test (PFT). PFT is commonly used to evaluate the severity and therapeutic response in COPD. However, complex mixture of COPD phenotypes requires a diagnostic tool with abilities to evaluate broader aspects of lung pathophysiology, and this is the primary reason why PFTs do not provide sufficient correlation with disease status and progression to serve as a reliable surrogate endpoint. What is needed is a quantitative and comprehensive set of COPD biomarkers that can provide phenotyping and staging of COPD, rapid assessment of response to a broad range of therapies, and tracking the progression of disease. The hope is that the hyperpolarized xenon magnetic resonance imaging (HXe MRI) could diagnose and intervene patients at the earliest stages of COPD, guide the selection of appropriate therapies, and extend life. In this proposal, two HXe MRI assessments will be performed. (1) A single sequence that combines a high-resolution image of inhaled HXe with a proton image acquired in the same breath-hold will provide the fraction of the lung volume with compromised airflow. (2) A new imaging protocol that exploits xenon's chemical shift sensitivity to the separate tissue compartments of the lung allows a detailed mapping of gas exchange through lung tissue and into the red blood cells. We hypothesize that these HXe MRI signatures will access physiologic information that were previously inaccessible by the conventional PFT and multimodality CT of chest, (MDCT). We also hypothesize that these imaging signatures will enhance our ability to evaluate COPD phenotypes and disease status better than the PFT and MDCT. Higher HXe MRI resolution based on the anatomy of the lung will further enhance the diagnostic sensitivity and specificity. In aim 1, we will perform a study of the correlation of imaging signatures of COPD with conventional assessments (PFT, MDCT and clinical outcomes). In aim 2, we will evaluate changes in the lung physiology of the patients with well-characterized COPD after being serially treated with three standard COPD therapies, long acting muscarinic antagonist (umeclidinium) and long acting beta-agonist (vilanterol) to improve ventilation, and inhaled corticosteroid (fluticasone) to potentially affect the inflammation in tissues. Our study design offers both cross-sectional and longitudinal information. Eighty treatment-nave subjects will be evaluated at baseline, after two serial 30-day courses of umeclidinium/vilanterol and fluticasone. The 320 assessments, considered independently, will determine correlations between functional imaging signatures and conventional metrics which include PFT, MDCT, and clinical outcomes. Within-subject temporal alterations of the HXe MRI imaging will be evaluated as potential biomarkers to assess COPD phenotypes and disease status, both of which we anticipate to deepen our basic mechanisms contributing to the genesis of COPD and to promote development of new strategies to diagnose and treat COPD.